The intrauterine period is critically important for brain development and may influence mental health throughout life. Animal studies have shown that psychosocial stress during pregnancy, especially in early and mid-stages of gestation, lead to neurobehavioral problems associated with suboptimal Central Nervous System (CNS) development involving motor skills, arousal, impulsivity, and emotional dysregulation. Yet, these studies cannot be directly applied to humans. The overall goal of the proposed study is driven by the hypothesis that exposure to psychosocial stress in utero can program changes in the functioning of the offspring's CNS during sensitive windows of fetal development, leading to neurodevelopmental impairment. This study builds upon our on-going NIH-funded study which assesses prenatal stress as a critical neurodevelopmental risk factor. The participants (N=408) reside in Queens/Long Island, where Superstorm Sandy caused devastation, allowing us to conduct a natural experiment of stress during pregnancy. Capitalizing on existing infrastructure, an established biorepository, and prospectively collected data on Sandy-related trauma after the disaster (severity, timing of exposure, duration of adversity, and psychological reactions), and normative (from everyday life) psychosocial stress experienced during pregnancy, we propose to 1) follow offspring through 42 months of age to evaluate key areas of neurodevelopment as a function of their exposure to prenatal stress; 2) evaluate whether timing of exposure to Sandy trauma is associated with different neurodevelopmental trajectories; 3) examine the inter- relations of prenatal stress, child neurodevelopment, and epi/genetic (methylation and gene expression) regulation of candidate genes, encompassing 5 key stress modulation and neuro-development pathways in paired samples of placenta and cord blood, and further explore if epigenetic regulation in those genes induce different trajectories of neurodevelopment; 4) explore stability of epigenetic marks during early development in childhood. Given the distinct biological functions and tissue- and developmental stage-specificity of gene regulation, assessment of epi/genetic marks in paired samples of placenta and cord blood at birth and saliva in childhood could help clarify disease mechanism. By demonstrating the utility of less invasive ways to collect peripheral tissues at different times in life, the study will advance the design for future epidemiologic studies, and potentially improve prognosis and interventions for developmental psychopathology. Using structural equation modeling, multilevel growth curve modeling, and hierarchical linear models, we will elucidate the underlying mechanisms of suboptimal neurodevelopment in early childhood, in association with maternal psychosocial stress exposure (types, intensity, and timing) during the course of pregnancy. The study will ultimately help us chart the course of mental disorders from in utero to birth and early childhood, further our understanding of the critical periods of pregnancy and their effect on a molecular level in humans, and set the stage for research into early interventions that could preempt mental disorders that might emerge later in life.